This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Axcex2-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to xcex2-amyloid production such as Alzheimer""s disease and Down""s Syndrome.
Alzheimer""s disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotionally stability. AD is a common cause of progressive dementia in humans and is one of the major causes of death in the United States. AD has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available (for review, Dennis J. Selkoe; Cell Biology of the amyloid (beta)-protein precursor and the mechanism of Alzheimer""s disease, Annu Rev Cell Biol, 1994, 10: 373-403).
Histopathological examination of brain tissue derived upon autopsy or from neurosurgical specimens in effected individuals revealed the occurrence of amyloid plaques and neurofibrillar tangles in the cerebral cortex of such patients. Similar alterations were observed in patients with Trisomy 21 (Down""s syndrome), and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type. Neurofibrillar tangles are nonmembrane-bound bundles of abnormal proteinaceous filaments and biochemical and immunochemical studies led to the conclusion that their principle protein subunit is an altered phosphorylated form of the tau protein (reviewed in Selkoe, 1994).
Biochemical and immunological studies revealed that the dominant proteinaceous component of the amyloid plaque is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids. This protein was designated Axcex2, xcex2-amyloid peptide, and sometimes xcex2/A4; referred to herein as Axcex2. In addition to its deposition in amyloid plaques, Axcex2 is also found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. Axcex2 was first purified and a partial amino acid reported in 1984 (Glenner and Wong, Biochem. Biophys. Res. Commun. 120: 885-890). The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No 4,666,829.
Compelling evidence accumulated during the last decade revealed that Axcex2 is an internal polypeptide derived from a type 1 integral membrane protein, termed xcex2 amyloid precursor protein (APP). xcex2 APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans. Axcex2 is derived from cleavage of xcex2 APP by as yet unknown enzyme (protease) system(s), collectively termed secretases.
The existence of at least four proteolytic activities has been postulated. They include xcex2 secretase(s), generating the N-terminus of Axcex2, xcex1 secretase(s) cleaving around the 16/17 peptide bond in Axcex2, and xcex3 secretases, generating C-terminal Axcex2 fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
Several lines of evidence suggest that abnormal accumulation of Axcex2 plays a key role in the pathogenesis of AD. Firstly, Axcex2 is the major protein found in amyloid plaques. Secondly, Axcex2 is neurotoxic and may be causally related to neuronal death observed in AD patients. Thirdly, missense DNA mutations at position 717 in the 770 isoform of xcex2 APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of AD. In addition, several other xcex2 APP mutations have been described in familiar forms of AD. Fourthly, similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human xcex2 APP. Fifthly, individuals with Down""s syndrome have an increased gene dosage of xcex2 APP and develop early-onset AD. Taken together, these observations strongly suggest that Axcex2 depositions may be causally related to the AD.
It is hypothesized that inhibiting the production of Axcex2 will prevent and reduce neurological degeneration, by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with Axcex2 production. One method of treatment methods would therefore be based on drugs that inhibit the formation of Axcex2 in vivo.
Methods of treatment could target the formation of Axcex2 through the enzymes involved in the proteolytic processing of xcex2 amyloid precursor protein. Compounds that inhibit xcex2 or xcex3 secretase activity, either directly or indirectly, could control the production of Axcex2. Advantageously, compounds that specifically target xcex3 secretases, could control the production of Axcex2. Such inhibition of xcex2 or xcex3 secretases could thereby reduce production of Axcex2, which, thereby, could reduce or prevent the neurological disorders associated with Axcex2 protein.
As evidenced by the interest in the treatment of neurological disorders related to xcex2-amyloid production, such as Alzheimer""s disease and Down""s Syndrome, a wide variety of compounds which inhibit Axcex2 protein production have been studied. For example, PCT publication number WO 98/28268 describes compounds of the general formula: 
as inhibitors of xcex2-amyloid peptide release and having utility in treating Alzheimer""s disease. Though some of the present compounds of this invention appear to fall within the generic description of the above publication, they are not specifically disclosed, suggested, or claimed therein.
Thus, it is desirable to develop additional inhibitors of Axcex2 protein production to treat Alzheimer""s disease or Down""s syndrome. The present invention discloses compounds of enhanced activity in inhibiting Axcex2 protein production.
One object of the present invention is to provide novel compounds which are useful as inhibitors of the production of Axcex2 protein or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating degenerative neurological disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of Formula (I): 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein R1, R2, R3, n, Y and Z are defined below, are effective inhibitors of the Axcex2 protein-production.
[1] In a first embodiment, the present invention provides a novel compound of Formula (I): 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is C1-C6 alkyl substituted with 0-3 R1a; C6-C10 aryl substituted with 0-3 R1b; C3-C6 cycloalkyl substituted with 0-3 R1b; or 5 to 10 membered heterocycle substituted with 0-3 R1b;
R1a, at each occurrence, is independently selected from: H, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16; C3-C10 carbocycle substituted with 0-3 R1b; C6-C10 aryl substituted with 0-3 R1b; and 5 to 10 membered heterocycle substituted with 0-3 R1b;
R1b, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, N3, NO2, NR15R16, phenoxy, C1-C4 thioalkoxy and CF3;
R5 is C1-C4 alkyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutyl, cyclobutylmethyl, or cyclobutylethyl;
R3, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
n is 0, 1, 2, or 3;
Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is C1-C3 alkyl substituted with 0-2 R12; C6-C10 aryl substituted with 0-4 R12b; C3-C10 carbocycle substituted with 0-2 R12; or C5-C10 membered heterocycle substituted with 0-4 R12b;
R12 is C6-C10 aryl substituted with 0-4 R12b; or C3-C10 carbocycle substituted with 0-2 R12;
R12b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C6 thioalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl), and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl); and
R19b is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or phenethyl.
[2] In a more preferred embodiment, the present invention provides for a compound of Formula I, 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is C1-C6 alkyl substituted with 0-1 R1a; C3-C6 cycloalkyl substituted with 0-1 R1b; phenyl substituted with 0-2 R1b; naphthyl substituted with 0-2 R1b; or pyridyl substituted with 0-2 R1b;
R1a, at each occurrence, is independently selected from: H, CF3, OR14, Cl, F, Br, I; C3-C10 carbocycle substituted with 0-3 R1b; and C6-C10 aryl substituted with 0-3 R1b;
R1b, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, C1, F, Br, I, CN, NO2, N3, SCH3, NR15R16, phenoxy, and CF3;
R5 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropylmethyl, or cyclobutylmethyl;
R3, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, Cl, F, Br, I, CN, NO2, and CF3;
n is 0, 1, or 2;
Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is C1-C3 alkyl substituted with 0-2 R12; or C6-C10 aryl substituted with 0-4 R12b;
R12 is C6-C10 aryl substituted with 0-4 R12b; or C3-C6 carbocycle substituted with 0-4 R12b;
R12b, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, SCH3, NR15R16, and CF3;
R14 is H, phenyl, benzyl, or C1-C6 alkyl;
R15, at each occurrence, is independently selected from H, C1-C4 alkyl, benzyl, and phenethyl; and
R16, at each occurrence, is independently selected from H, C1-C4 alkyl, benzyl, and phenethyl.
[3] In an even more preferred embodiment, the present invention provides for a compound of Formula I, 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, naphthyl, pyridyl; methyl substituted with 1 R1a; ethyl substituted with 1 R1a; or phenyl substituted with 1-3 R1b;
R1a, at each occurrence, is independently selected from: H, CF3, OR14, Cl, F, Br, I; C3-C6 cycloalkyl substituted with 0-3 R1b; and phenyl substituted with 0-3 R1b;
R1b, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, Cl, F, Br, I, CN, NO2, N3, SCH3, NR15R16, phenoxy, and CF3;
R5 is methyl;
R3, at each occurrence, is independently selected from H, OH, methyl, ethyl, methoxy, ethoxy, Cl, F, Br, I, CN, NO2, and CF3;
n is 0 or 1;
Y is a bond or xe2x80x94Oxe2x80x94;
Z is C1-C3 alkyl substituted with 0-2 R12; or phenyl substituted with 0-3 R12b;
R12 is C3-C6 cycloalkyl substituted with 0-3 R12b; phenyl substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, SCH3, C1-C2 haloalkyl, C1-C2 haloalkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, methyl, ethyl, phenyl, or benzyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, benzyl, and phenethyl; and
R16, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, benzyl, and phenethyl.
[4] In another embodiment, the present invention provides for a compound of Formula (Ia), 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is methyl substituted with 1 R1a; ethyl substituted with 1 R1a; phenyl substituted with 1-3 R1b; methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, naphthyl, or pyridyl;
R1a is phenyl substituted with 0-3 R1b; cyclopropyl substituted with 0-1 R1b; cyclobutyl substituted with 0-1 R1b; cyclopentyl substituted with 0-1 R1b; or cyclohexyl substituted with 0-1 R1b;
R1b, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, Cl, F, Br, I, CN, NO2, N3, SCH3, phenoxy, and CF3;
Z is methyl substituted with R12; or phenyl substituted with 0-2 R12b;
R12 is phenyl substituted with 0-2 R12b;
R12b, at each occurrence, is independently selected from H, OH, methyl, ethyl, methoxy, ethoxy, Cl, F, Br, I, CN, NO2, SCH3, NR15R16, OCF3, and CF3;
R15, at each occurrence, is independently selected from H, methyl, and ethyl; and
R16, at each occurrence, is independently selected from H, methyl, and ethyl.
[5] In an even more preferred embodiment, the present invention provides for a compound Formula (Ib); 
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclobutyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2-cyclopentyl, xe2x80x94CH2CH2-cyclopropyl, xe2x80x94CH2CH2-cyclobutyl, xe2x80x94CH2CH2cyclohexyl, xe2x80x94CH2CH2cyclopentyl, phenylmethyl, 2-chlorophenylmethyl, 2-fluorophenylmethyl, 2-bromophenylmethyl, 2-hydroxyphenylmethyl, 2-nitrophenylmethyl, 2-methylphenylmethyl, 2-methoxyphenylmethyl, 2-phenoxyphenylmethyl, 2-trifluoromethylphenylmethyl, 3-hydroxyphenylmethyl, 3-nitrophenylmethyl, 3-fluorophenylmethyl, 3-chlorophenylmethyl, 3-bromophenylmethyl, 3-thiomethoxyphenylmethyl, 3-methylphenylmethyl, 3-trifluoromethylphenylmethyl, 3-methoxyphenylmethyl, 4-chlorophenylmethyl, 4-bromophenylmethyl, 4-nitrophenylmethyl 4-methylphenylmethyl, 4-hydroxyphenylmethyl, 4-methoxyphenylmethyl, 4-ethoxyphenylmethyl, 4-butoxyphenylmethyl, 4-iso-propylphenylmethyl, 4-trifluoromethylphenylmethyl, 4-azidophenylmethyl, 4-cyanophenylmethyl,4-ethylphenylmethyl, 4-fluorophenylmethyl, 4-iodophenylmethyl, 2,3-dichlorophenylmethyl, 2,5-difluorophenyl, 2,3-difluorophenylmethyl, 2,4-dichlorophenylmethyl, 2,5-dimethoxyphenylmethyl, 3,4-dichlorophenylmethyl, 3,4-difluorophenylmethyl, 3,4-dimethoxyphenylmethyl, 3,5-difluorophenylmethyl, 3,5-dichlorophenylmethyl, 3,5-di-(trifluoromethyl)phenylmethyl, 3,5-dimethoxyphenylmethyl, 2,4-difluorophenylmethyl, 2,6-difluorophenylmethyl, 2,5-difluorophenylmethyl, 2-fluoro-3-trifluoromethylphenylmethyl, 4-fluoro-2-trifluoromethylphenylmethyl, 2-fluoro-4-trifluoromethyl-phenylmethyl, 2-choro-6-fluorophenylmethyl, 2-fluoro-6-chlorophenylmethyl, 2,5-dimethylphenylmethyl, 2-fluoro-3-trifluoromethylphenylmethyl, 3-(trifluoromethyl)-(4-chloro-phenylmethyl, 3-chloro-4-cyano-phenylmethyl, 3-chloro-4-iodo-phenylmethyl, 3,4,5-trichlorophenylmethyl, 3,4,5-trifluorophenylmethyl, 3,4,5-trimethoxyphenylmethyl, 3,4,5-tri(trifluoromethyl)phenylmethyl, 2,4,6-trifluorophenylmethyl, 2,4,6-trimethylphenylmethyl, 2,4,6-tri-(trifluoromethyl)phenylmethyl, 2,3,5-trifluorophenylmethyl, 2,4,5-trifluorophenylmethyl, 2-phenylethyl, 2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl, (1-phenyl)ethyl, 1-(p-chorophenyl)ethyl, (1-trifluoromethyl)phenylethyl, (4-methoxyphenyl)ethyl, 1-naphthyl, 2-naphthyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl; and
Z is is phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, or 4-CF3O-phenyl.
[6] In another more preferred embodiment the present invention provides for a compound of Formula (I) which is 
or a pharmaceutically acceptable salt or prodrug thereof.
[7] In a second embodiment the present invention provides for pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
[8] In a third embodiment the present invention provides for a method for the treatment of neurological disorders associated with xcex2-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I).
[9] In a fifth embodiment the present invention provides for a method for inhibiting xcex3-secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits xcex3-secretase activity.
As used herein, the term xe2x80x9cAxcex2xe2x80x9d denotes the protein designated Axcex2, xcex2-amyloid peptide, and sometimes xcex2/A4, in the art. Axcex2 is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids found in amyloid plaques, the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No 4,666,829. The 43 amino acid sequence is:
The term xe2x80x9cAPPxe2x80x9d, as used herein, refers to the protein known in the art as xcex2 amyloid precursor protein. This protein is the precursor for Axcex2 and through the activity of xe2x80x9csecretasexe2x80x9d enzymes, as used herein, it is processed into Axcex2. Differing secretase enzymes, known in the art, have been designated xcex2 secretase, generating the N-terminus of Axcex2, xcex1 secretase cleaving around the 16/17 peptide bond in Axcex2, and xe2x80x9cxcex3 secretasesxe2x80x9d, as used herein, generating C-terminal Axcex2 fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is an keto (i.e. xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g. R12) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R12, then said group may optionally be substituted with up to two R12 groups and R12 at each occurrence is selected independently from the definition of R12. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, xe2x80x9cC1-C6 alkylxe2x80x9d, denotes alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. Preferred xe2x80x9calkylxe2x80x9d group, unless otherwise specified, is xe2x80x9cC1-C4 alkylxe2x80x9d. Additionally, unless otherwise specified, xe2x80x9cpropylxe2x80x9d denotes n-propyl or i-propyl; xe2x80x9cbutylxe2x80x9d denotes n-butyl, i-butyl, sec-butyl, or t-butyl.
As used herein, xe2x80x9calkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. Examples of xe2x80x9cC2-C6 alkenylxe2x80x9d include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, hexenyl, and the like.
As used herein, xe2x80x9calkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d or xe2x80x9calkyloxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy. Similarly, xe2x80x9calkylthioxe2x80x9d or xe2x80x9cthioalkoxyxe2x80x9d is represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo. Unless otherwise specified, preferred halo is fluoro and chloro. xe2x80x9cCounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl. xe2x80x9cHaloalkoxyxe2x80x9d is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, and the like. xe2x80x9cHalothioalkoxyxe2x80x9d is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, having the specified number of carbon atoms. For example, xe2x80x9cC3-C6 cycloalkylxe2x80x9d denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
As used herein, xe2x80x9ccarbocyclexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Preferred xe2x80x9ccarbocyclexe2x80x9d are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic ringxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, and tetrazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, the term xe2x80x9carylxe2x80x9d, xe2x80x9cC6-C10 arylxe2x80x9d or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl. Preferred xe2x80x9carylxe2x80x9d is phenyl. Unless otherwise specified, xe2x80x9carylxe2x80x9d may be unsubstituted or substituted with 0 to 3 groups selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, amino, hydroxy, Cl, F, Br, I, CF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94N(CH3)2, N(CH3)H, CN, NO2, OCF3, C(xe2x95x90O)CH3, CO2H, CO2CH3, or C1-C4 haloalkyl.
The compounds herein described may have asymmetric centers. One enantiomer of a compound of Formula (I) may display superior biological activity over the opposite enantiomer. For example carbon 3 of lactam ring of Formula (Ixe2x80x2) may exist in either an S or R configuration. Thus, for example, both R or S configurations at carbon 3 in Formula (Ixe2x80x2-3R) and (Ixe2x80x2-3S) are considered part of the invention. Examples of such configuration include, but are not limited to, 
The (S)xe2x80x94configuration at carbon 3 of the lactam ring is preferred.
When required, separation of the racemic material can be achieved by methods known in the art. Additionally, the carbon atom to which R5 is attached may display superior biological activity over the opposite enantiomer. For example, when R5 is C1-C4 alkyl, the configuration of the carbon may be described as R or S. All configurations are considered part of the invention; however, the S configuration of the carbon bearing R5 is more preferred.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of Formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and acetamide, formamide and benzamide derivatives of amine functional groups in the compounds of Formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
A variety of compounds of Formula (I) can be prepared by methods described in Scheme 1. The protected xcex1-amine 2 of the xcex1-amino-xcex5-caprolactam 1 can be prepared by methods well known in the literature for amino protecting groups as discussed in Theodora W. Greene""s book xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, like N-Boc using di-t-butyldicarbonate in an appropriate solvent like DMSO. The lactam nitrogen of compound 2 can be alkylated to give compound 3 by generating the anion with bases such as LDA, lithium bis(trimethylsilyl)amide or sodium hydride in solvents like THF, with or without co-solvents such as DMPU or HMPA and reacting this with a variety of groups, each of which containing a leaving groups (LG) such as a bromide, iodide, mesylate or tosylate. Alkylating agents such as xcex1-bromo amides, ketones and acids can be prepared by a number of literature methods including halogenation of amino acids by diazotization or are commercially available. Other suitable alkylating agents such as alkyl, allylic and benzylic halides can be formed form a variety of precursors such as free-radical addition of halides or activation of alcohols, and other chemistries known to those skilled in the art. For discussion of these types of reactions, see Carey, F. A. and Sundberg, R. J., Advanced Organic Chemistry, Part A, New York: Plenum Press, 1990, pages 304-305, 342-347, 695-698.
The N-Boc protecting group of compound 3 can be removed by any number of methods well known in the literature like TFA in methylene chloride to give an amine 4. The amine 4 can be coupled to an appropriately substituted carboxylic acid 5 or acid chloride by methods well described in the literature for making amide bonds, like TBTU in DMF with a base like NMM to give an elaborated compound of Formula (I).
Appropriate carboxylic acid 5 is available through the chemistry shown in Scheme 2. Thus, coupling of an amino acid ester 5b under standard conditions including Schotten-Bowman conditions produces an amide 5a. The carboxylic acid 5 is available through saponification of the ester 5a under standard basic conditions. Alternatively, the amide 5a can be formed using the amino acid ester 5b and a carboxylic acid using any of the standard coupling agents mentioned above or known to one skilled in the art. 
Methods for the synthesis of lactams and alkylation of lactams are known in the art and are disclosed in a number of references including PCT publication number WO 98/28268 (published Jul. 2, 1998) and PCT publication number WO 00/07995 (published Feb. 17, 2000), which are hereby incorporated in their entirety by reference.
Chemical abbreviations used in the Examples are defined as follows: xe2x80x9cDMPUxe2x80x9d for 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, xe2x80x9cTBTUxe2x80x9d for O-(1H-benzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate, xe2x80x9cHATUxe2x80x9d for O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetrmethyluronium hexafluorophosphate, xe2x80x9cTFAxe2x80x9d for trifluoroacetic acid, xe2x80x9cNMMxe2x80x9d for n-methylmorpholine, and xe2x80x9cBOPxe2x80x9d for benzotriazol-1-yloxytris-(dimethylamino-phosphonium hexafluorophosphate. xe2x80x9cHPLCxe2x80x9d is an abbreviation used herein for high pressure liquid chromatography.
Using conditions generally known to one skilled in the art, compounds of the present invention are generally purified by HPLC. Reverse-phase HPLC can be carried out using a Vydac C-18 column with gradient elution from 10% to 100% buffer B in buffer A (buffer A: water containing 0.1% trifluoroacetic acid, buffer B: 10% water, 90% acetonitrile containing 0.1% trifluoroacetic acid). If necessary, organic layers can be dried over sodium sulfate unless otherwise indicated. However, unless otherwise indicated, the following conditions are generally applicable.